Fever of Unknown Origin and Adult Onset Still s Disease (AOSD)

AM Report Eric Edwards, M.D. September 4, 2007

Fever of Unknown Origin: Definition

NOT febrile illness without initially obvious etiology Classical definition (Petersdorf and Beeson, 1961):
Fever > 38.3 on several occasions Duration>3 weeks Failure to reach a diagnosis after one week of inpatient investigation*
*or at least 3 outpatient visits (refined definition)

Patient Subtypes
Classical Nosocomial (Hospitalized>24h, no fever PTA)
C. Difficile, PE, drugs

Immune Deficient (ANC<500)

Bacteremia, Fungal, HSV

HIV
M. Avium, PCP, CMV, lymphoma, Kaposi s, drugs

Differential Diagnosis
Infections Malignancies Autoimmune Disease Miscellaneous
Drugs Hepatitis DVT

Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.

Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.

Causes of FUO
(in India)

Infectious 53%
#1: TB (45%)

Unknow n 14% Misc. 5% Other Rheum 6% SLE 5% Other Onc 9% NHL 8%

TB 24%

Neoplasm: 17%
#1: NHL (47%)

Collagen Vasc.: 11%

#1 SLE: 45%

Abscess 7% Endocarditis 5% Other ID 17%

Miscellaneous: 5% Undiagnosed: 14%

Kejariwal D et al. J Postgrad Med. 2001 Apr-Jun; 47(2): 104-7.

FUO by the Decades

U nk nown 9%

U nknown 17%
I nf e c t i ous 36%

I nf ect i ous 31%

Ot he r 18%

Ot her 13%

R he um 18% M a l i gna nc y 19%

R heum 15% M al i gnancy

1950s
U nknown 17% I nf ect i ous 29%
U nknown 29%

1970s

24%

I nf ect i ous 24%

Ot her 13%
M al i gnancy Ot her 15%

M al i gnancy R heum 25% 16%

8% R heum 24%

1980s
Mourad O et al. Arch Int Med. 2003 Mar 10;163(5):545-51.

1990s

Minimal Diagnostic Criteria

H+P CBC & Diff Blood Cultures x 3 Chem10 LFTs U/A and Microscopy Urine culture Chest X-ray XHepatitis serologies (if abnormal LFTs)

Other Basic Tests

ESR/CRP Peripheral Smear ANA Rheumatoid Factor HIV CMV IgM Mono Spot PPD

Imaging
Abdominal CT Chest CT Nuclear Imaging Lower Extremity Dopplers TTE/TEE

Invasive Procedures
Lumbar Puncture Liver Biopsy Temporal Artery Biopsy Bone Marrow Biopsy Lymph Node Biopsy Surgical Exploration of the Abdomen

Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.

Adult Onset Still s Disease

Epidemiology
Rare (0.16/100000) ~60% female Affects all ages

Pathogenesis
Poorly understood Genetic component? Infectious trigger?

Characteristics
Daily, high spiking fevers (85-100%) (85Arthritis (68-94%) (68Evanescent rash (51-87%) (51-

No specific diagnostic study Diagnosis is based on the presentation of characteristic features and the exclusion of similar conditions

Diagnostic Criteria (Yamaguchi)

Major
Fever>39, lasting >1 Fever>39 week Arthralgias or arthritis lasting >2 weeks Typical rash WBC>10,000 with >80% PMNs

Minor
Sore throat Lymphadenopathy and/or splenomegaly Abnormal LFTs Negative ANA and RF

Exclusions
Infections Malignancy Rheumatic Disease

Diagnosis: Five criteria, at least two major (83-91% sens., 90% spec., 70% PPV, 95% NPV)

AOSD and Ferritin

Ferritin is an acute phase reactant 80% have >5x elevation in ferritin NonNon-specific Low Glycosylated ferritin (GF) is more specific
GF<20% + Ferritin >5x nl=93% specific
Only 43% sensitive

Treatment
NSAIDs
Monotherapy is effective in only ~10%

Steroids
75% will respond favorably

Methotrexate TNF blocking agents

Etanercept Infliximab

Prognosis
Three distinct patters (~1:1:1)
Self limited
Most patients achieve remission within one year

Intermittent
Recurrent flares with complete remission between Flares may be years apart Recurrences tend to be milder than initial episode

Chronic
Articular manifestations can be severe
2/3 may need at least one total joint replacement

References
1. Roth AR et al. Approach to the Patient with Fever of Unknown Origin. Am Fam Physician. 2003 Dec 1;68(11):2223-28. 1;68(11):22232. Mourad O et al. A Comprehensive Evidence Based Approach to Fever of Unknown Origin. Arch Int Med. 2003 Mar 10;163:545-51. 10;163:5453. Bor, DH. Approach to the Adult with Fever of Unknown Origin. www.utdol.com. www.utdol.com. 4. Kejariwal D et al. Pyrexia of Unknown Origin: A Prospective Study of 100 Cases. J Postgrad Med. 2002 Apr-Jun;48(2):155-6. Apr-Jun;48(2):1555. Efthimiou P et al. Diagnosis and Management of Adult Onset Still s Disease. Ann Rheum Dis. 2006 May;65:564-72. May;65:5646. Uppal SS et al. Ten Years of Clinical Experience with Adult Onset Still s Disease: Is the Outcome Improving? Clin Rheumatol. 2007 Jul;26(7):1055-60. Jul;26(7):1055-